Imipenem monohydrate of Formula I which is the N-formimidoyl derivative of thienamycin and has the structural Formula I.
It is the first clinically available member of a new class of β-lactam antibiotics that possess the carbapenem ring system. Imipenem exhibits an extremely broad spectrum of activity against gram-positive and gram-negative aerobic and anaerobic species, which is partly due to its high stability in the presence of β-lactamases.
Imipenem was first disclosed in U.S. Pat. No. 4,194,047. Several general methods for the preparation of N-methylene derivatives of thienamycin including imipenem have been outlined in U.S. Pat. No. 4,194,047 starting from thienamycin. The process for the preparation of imipenem has been found to give the product in low yield and of poor quality due to inherent instability of the starting compound i.e. thienamycin.
U.S. Pat. No. 4,292,436 provides an alternate method for the preparation of imipenem from bicyclo ketone precursor of Formula II,
wherein R is a protecting group, comprising activating the keto ester and reacting the activated keto ester with N-formimidoyl-2-aminoethanethiol to obtain carboxyl protected imipenem which gives imipenem after hydrogenation. However, the process gives low yields of the final product (59% in solution and 35% of isolated imipenem monohydrate).
U.S. Pat. No. 4,374,772 gives an improved process for preparing imipenem from dilute aqueous solutions of thienamycin using benzylic formimidate reagents. However, the process has the disadvantage of producing at least 5% of dimmer bis-thienamycin formamidene along with the desired proudct imipenem.
U.S. Pat. No. 4,894,450 uses new reagents—bis (chloro-substituted phenyl) phosphorochloridate to activate the bicycloketone precursor of formula II, wherein R is a protecting group. Subsequent reaction with cysteamine hydrochloride, amidine formation and hydrogenolysis of the ester group gives good yield of imipenem. However, the reagent employed for activation is not available commercially and its preparation involves a cumbersome multistage purification process.
In light of the above drawbacks in the prior art processes, there is a need for the development of a process for the preparation of imipenem which is convenient to operate on an industrial scale, employs readily and commercially available raw materials and reagents and which process gives substantially pure product in good yield.